U.S. patent application number 12/490968 was filed with the patent office on 2009-10-22 for biodegradable block copolymeric compositions for drug delivery.
This patent application is currently assigned to Protherics Salt Lake City, Inc.. Invention is credited to Chung Shih, Gaylen M. Zentner.
Application Number | 20090264537 12/490968 |
Document ID | / |
Family ID | 29779889 |
Filed Date | 2009-10-22 |
United States Patent
Application |
20090264537 |
Kind Code |
A1 |
Shih; Chung ; et
al. |
October 22, 2009 |
BIODEGRADABLE BLOCK COPOLYMERIC COMPOSITIONS FOR DRUG DELIVERY
Abstract
An improved drug delivery composition and method of use is
disclosed. The composition comprises one or more biodegradable
block copolymer drug carriers; and a reconstitution enhancing and
enabling agent comprising polyethylene glycol (PEG), a PEG
derivative or a mixture of PEG and a PEG derivative. The
composition can be administered as is or after being be dissolved
or rapidly reconstituted in an aqueous vehicle to afford a
homogeneous solution or uniform colloidal systems.
Inventors: |
Shih; Chung; (Sandy, UT)
; Zentner; Gaylen M.; (Salt Lake City, UT) |
Correspondence
Address: |
HUNTON & WILLIAMS LLP;INTELLECTUAL PROPERTY DEPARTMENT
1900 K STREET, N.W., SUITE 1200
WASHINGTON
DC
20006-1109
US
|
Assignee: |
Protherics Salt Lake City,
Inc.
West Valley City
UT
|
Family ID: |
29779889 |
Appl. No.: |
12/490968 |
Filed: |
June 24, 2009 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10186462 |
Jun 28, 2002 |
|
|
|
12490968 |
|
|
|
|
10167768 |
Jun 11, 2002 |
|
|
|
10186462 |
|
|
|
|
Current U.S.
Class: |
514/772.1 |
Current CPC
Class: |
C08L 71/02 20130101;
C08G 2261/126 20130101; A61P 35/00 20180101; A61K 31/765 20130101;
A61K 47/10 20130101; A61K 47/34 20130101; A61P 3/10 20180101; A61K
31/77 20130101; A61K 9/0024 20130101; C08L 71/02 20130101; C08L
2666/18 20130101; C08L 71/02 20130101; C08L 2666/02 20130101 |
Class at
Publication: |
514/772.1 |
International
Class: |
A61K 47/34 20060101
A61K047/34 |
Claims
1-7. (canceled)
8. A composition comprising: 1) one or more biodegradable block
copolymer drug carriers comprising A-B, A-B-A or B-A-B block
copolymers having a total weight average molecular weight of 2000
to 4990 Daltons, wherein the A block is a biodegradable polyester
or poly(ortho ester) and the B block is polyethylene glycol (PEG),
and the weight percentage of the A block is between 51% to 83% and
the weight percentage of the B block is between 17% to 49%; and 2)
a polyethylene glycol (PEG), a PEG derivative, or a mixture of PEG
and a PEG derivative, said PEG or PEG derivative having a molecular
weight of 150 to 1100 Daltons; wherein at least one of the
biodegradable block copolymeric drug carriers is soluble in an
aqueous solution and miscible with the PEG, PEG derivatives, or
mixtures thereof; wherein the weight ratio of the biodegradable
block copolymeric drug carrier and the PEG, PEG derivative or
mixtures thereof is within the range of 5:1 to 1:99 and wherein
said composition can be reconstituted in water or an aqueous
solution to form a homogeneous solution or an uniform colloidal
system within 0.01 minutes to 180 minutes; and wherein the
composition possesses reverse thermal gelation properties.
9. The composition according to claim 8, wherein the PEG derivative
is an ester derivatized PEG wherein the PEG is derivatized with
D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid,
L-lactic acid, glycolide, glycolic acid, .epsilon.-caprolactone,
1,4-dioxan-2-one, .epsilon.-hydroxy hexanoic acid,
.gamma.-butyrolactone, .gamma.-hydroxy butyric acid,
.delta.-valerolactone, .delta.-hydroxy valeric acid, hydroxybutyric
acids, malic acid, or mixtures thereof.
10. The composition according to claim 8 wherein the PEG derivative
is an ortho ester derivatized PEG.
11. The composition according to claim 8, wherein the PEG
derivative is represented by
R.sup.1--CO--O--(CH.sub.2--CH.sub.2--O).sub.n--CO--R.sup.2 or
R.sup.1--O--(CH.sub.2--CH.sub.2--O).sub.n--R.sup.2-- wherein
R.sup.1 and R.sup.2 are independently H or C.sub.1 to C.sub.10
alkyl and n is an integer between 3 and 20.
12-13. (canceled)
14. The composition according to claim 8 further comprising a
drug.
15-41. (canceled)
Description
REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation-in-part of application
Ser. No. 10/167,768 filed Jun. 11, 2002.
FIELD OF THE INVENTION
[0002] The present invention relates to a composition for drug
delivery. More specifically, the present invention relates to a
copolymeric composition comprising a liquid polyethylene glycol
(PEG), a PEG derivative or a mixture of PEG and PEG derivative; and
a biodegradable block copolymeric drug carrier. Particularly, this
invention relates to compositions comprising a to polyethylene
glycol (PEG), PEG derivatives, or a mixture of a PEG and a PEG
derivative, and biodegradable ABA, BAB and AB type block copolymers
that are based on biodegradable hydrophobic polyester or poly(ortho
ester) A blocks and hydrophilic polyethylene glycol (PEG) B
blocks.
BACKGROUND OF THE INVENTION
[0003] Biodegradable polymers have been used as surgical sutures,
wound dressings, and as drug delivery systems. Among them,
polylactide (PLA), polyglycolide (PGA) and their copolymers (PLGA)
have attracted the most attention. One example of a biodegradable
polymeric drug delivery system is a system wherein a drug is
contained in a biodegradable polymer matrix that is surgically
implanted, which is a big disadvantage. In the form of injectable
drug delivery systems, polymeric microspheres and nanospheres are
known in the art. Commercially available drug delivery formulations
based on PLGA microspheres include Lupron Depot.RTM. and Nutropin
Depot.RTM.. Microsphere and nanosphere systems have disadvantages
in that they require special and complex preparation methods.
Unfortunately, manufacturing microsphere and nanosphere dosage
forms requires use of toxic or dangerous solvents (e.g., methylene
chloride, ethyl acetate) and elaborate procedures (e.g., double
emulsions, or cryogenic spraying techniques). The batch size is
usually small and the cost is high. In addition, since PLGA
biodegradable polymers used can only be dissolved in organic
solvents their preparation requires the use of such solvents which
are foreign and harmful to the human body, and cannot be completely
removed during manufacture by any known method. Furthermore, some
drugs such as peptides and proteins may lose their pharmacological
activity after contact with organic solvents.
[0004] An improvement to the aforementioned drug delivery systems
is an in situ formed depot based on PLGA as disclosed in U.S. Pat.
No. 5,599,552. In that system, PLGA is dissolved in water-soluble
organic solvent(s), such as N-methyl-2-pyrrolidone, and the drug is
either suspended or dissolved in this polymeric solution. The
solution can be injected subcutaneously to form an in situ depot to
trap the drug in the polymer that precipitates as the organic
solvent diffuses away. However, the drawback is the requirement for
an organic solvent that is used to dissolve the biodegradable PLGA
polymer. Organic solvents, such as N-methyl-2-pyrrolidone, are
foreign to the human body and can cause unwanted side effects both
acutely and chronically.
[0005] U.S. Pat. No. 5,543,158 discloses nanoparticles or
microparticles formed from a water-insoluble block copolymer
consisting essentially of poly(alkylene glycol) and poly(lactic
acid). The molecular weight of the block copolymer is high and the
copolymer is insoluble in water. In the nanoparticle or
microparticle, the biodegradable moieties of the copolymer are in
the core of the nanoparticle or microparticle and the poly(alkylene
glycol) moieties are on the surface of the nanoparticle or
microparticle in an amount effective enough to decrease uptake of
the nanoparticle or microparticle by the reticuloendothelial
system. Nanoparticles are prepared by dissolving the block
copolymer and drug in an organic solvent, forming an o/w emulsion
by sonication or stirring, and collecting the nanoparticles
containing the drug following precipitation.
[0006] Currently there are few synthetic or natural polymeric
materials that can be used for the controlled delivery of drugs,
including peptide and protein drugs, because of strict regulatory
compliance requirements such as biocompatibility, low toxicity,
having a clearly defined degradation pathway, and safety of the
polymers and degradation products. The most widely investigated and
advanced biodegradable polymers in regard to available
toxicological and clinical data are the aliphatic
poly(.alpha.-hydroxy acids), such as poly(D-, L-, or D, L-lactic
acid) (PLA), poly(glycolic acid) (PGA) and their copolymers (PLGA).
These polymers are commercially available and are presently used as
bioresorbable sutures and in biodegradable microsphere drug
delivery systems. FDA-approved microsphere systems for controlled
release of leuprolide acetate (Lupron Depot.TM.) and human growth
hormone (Nutropin Depot.TM.) are based on PLGA copolymers. Based on
this history of use, PLGA copolymers have been the materials of
choice in the initial design of parenteral controlled release drug
delivery systems using a biodegradable carrier.
[0007] Even though there has been some limited success,
biodegradable block copolymers that are based on biodegradable
polyester or poly(ortho ester) and polyethylene glycol (PEG)
blocks, when used as drug carriers, present problems that are
associated with their physicochemical properties and attendant
methods of fabrication. For example, biodegradable block copolymers
are, by design, not stable in aqueous environments although
shelf-lives of several years can be achieved when they are stored
frozen. However, elimination of cold storage requirements would be
advantageous in most instances. It is also desirable to gain
further advantages related to rapid dissolution of neat block
copolymers into aqueous vehicles at normal or ambient room
temperature conditions. Rapid dissolution of the block copolymers
permits reconstitution at time-of-use to occur, which in turn
permits room temperature storage of neat block copolymers. Known
water soluble block copolymers are slow to dissolve in water, often
requiring several hours for complete dissolution to occur.
Compositions that show accelerated dissolution kinetics are
desired.
[0008] Some drugs, such as proteins, are stable in aqueous
solutions for only short periods. To compensate for this short-term
stability, these drugs are commonly formulated as dry cakes and
powders that can be stored under water-free conditions for much
longer periods. Immediately prior to administration the dry cake or
powder is reconstituted with an aqueous vehicle. Thus the situation
is frequently encountered where it is desirable to have both the
drug and the block copolymer drug delivery system formulated in
reconstitutable forms. To be facile, it is critical that
reconstitution, i.e., dissolution of the block copolymers and drug
be completed in a short period.
[0009] U.S. Pat. No. 5,384,333 discloses an injectable drug
delivery composition in which a pharmacologically active substance
is contained in a copolymer comprising a hydrophilic part and a
hydrophobic part. However, the composition has to be heated to a
relatively high temperature such as 38.degree. C. to 52.degree. C.,
immediately before use and it is difficult to uniformly distribute
the drug in the polymeric composition. U.S. Pat. No. 5,612,052
discloses a block copolymer composition that when contacted with
water forms a hydrogel. However, the drug incorporated in this
composition is rapidly released. U.S. Pat. No. 5,599,552 discloses
a composition wherein a water-insoluble biodegradable thermoplastic
polymer is dissolved in a water-miscible organic solvent, and the
resulting composition can be implanted where it then undergoes a
phase transition when in contact with water or body fluids.
However, the drawback is that it is difficult to use because a
mono-molecular organic solvent is used to dissolve the
biodegradable thermoplastic polymer. Most mono-organic solvents,
such as N-methyl-2-pyrrolidone, ethyl lactate, dimethylsulfoxide,
etc., cause side effects such as cell dehydration and tissue
necrosis, etc. and they may also cause severe pain at the
application sites.
[0010] U.S. Pat. No. 5,607,686 discloses a liquid polymeric
composition prepared by mixing a hydrophilic liquid polymer,
instead of a mono-molecular organic solvent, with a water-insoluble
hydrophobic polymer. When contacted with water the composition
undergoes a phase transition and forms an implant and thus it does
not cause a the rapid volume reduction and it has no special side
effects due to the good cyto-compatibility of the low molecular
weight polyethylene oxide. However, the water-insoluble hydrophobic
polymers used are not biodegradable. In addition, the preparation
of the composition requires heating to about 80.degree. C. in order
to achieve uniform mixing of the water-insoluble hydrophobic
polymer and the hydrophilic liquid polymer. Therefore, this system
may be suitable to use for adherence prevention and wound
protection without any physiologically active substance, but it is
not suitable for delivery of physiologically active substances,
particularly peptide or protein medicines because peptide and
protein medicines lose their activities at high temperatures.
Furthermore, protein medicines are water soluble, thus it is very
difficult to uniformly incorporate them into the composition. In
addition, it is not disclosed in this patent how the drugs or
physiologically active substances can be uniformly incorporated in
the polymeric composition. Particularly, although polylactide,
polyglycolide and their copolymers can be mixed with polyethylene
glycol at high temperatures of 80.degree. C. in order to obtain a
uniform composition, the composition undergoes phase separation
when it stands for a long period of time due the lowered affinity
of the polylactide, the polyglycolide or their copolymers with
polyethylene glycol. Therefore, it is very difficult to maintain a
uniform composition.
[0011] Sterilization steps are necessary in the preparation of
implant formulations. Existing sterilization methods are unsuitable
for sustained drug delivery formulations due to properties of the
implant compositions or because the methods are uneconomical or too
complicated. For example, it is almost impossible to prepare a
uniform solution by mixing a drug, a water-insoluble biodegradable
polymer and a hydrophilic polymer. Therefore, the composition
cannot be sterilized by simple methods such as membrane filtration.
Furthermore, although the formulation may be prepared under
sterilize conditions, such methods are very expensive to the extent
that the practicability of the preparation may be lowered.
[0012] Therefore, there is a need for a biodegradable drug delivery
composition that is a flowable liquid or can be rapidly
reconstituted in an aqueous vehicle to afford a homogeneous true
solution or uniform colloidal system in order to be easily prepared
and administered to provide improved drug delivery. Accordingly,
the present invention represents improved drug delivery
compositions that minimize or are free of the problems mentioned
above.
SUMMARY OF THE INVENTION
[0013] The present invention provides biodegradable compositions
for drug delivery and is a flowable liquid or can be rapidly
reconstituted in an aqueous vehicle to afford a homogeneous
solution or uniform colloidal system, and methods of use thereof
for preparing a pharmaceutically effective formulation for delivery
of drugs.
[0014] The present invention also provides a method for preparing
the biodegradable drug delivery composition and a method for
effectively administering such a composition to warm blooded
animals. The drug delivery composition of the present invention can
be administered directly to a warm blooded animal without an
aqueous vehicle, or can be administered after being rapidly
reconstituted in an aqueous vehicle to afford a homogeneous
solution or uniform colloidal system. The administration can be
done by any functional means such as parenteral, ocular,
inhalation, transdermal, vaginal, buccal, transmucosal,
transurethral, rectal, nasal, oral, peroral, pulmonary, topical or
aural and any other means of administration that may be compatible
with the present invention.
[0015] The composition of the present invention comprises: 1) one
or more biodegradable block copolymer drug carriers comprising A-B,
A-B-A or B-A-B block, wherein the A block is a biodegradable
polyester or poly(ortho ester) and the B block is polyethylene
glycol (PEG) and the weight percentage of the A block is between
20% to 99%; and 2) a polyethylene glycol (PEG), a PEG derivative,
or a mixtures of PEG and a PEG derivative, wherein the
biodegradable drug carrier is soluble in the liquid PEG and/or PEG
derivatives. The weight averaged molecular weight of the
biodegradable block copolymer of the present invention is
preferably within the range of 1,000 to 100,000 Daltons, more
preferably within the range of 1,000 to 50,000 Daltons and most
preferably within the range of 1,000 to 15,000 Daltons. Preferably,
the weight percentage of the hydrophobic A block in the
biodegradable block copolymer is between 20% to 99%, more
preferably 20-85%.
[0016] One embodiment of the present invention is a composition
comprises: 1) one or more biodegradable block copolymer drug
carriers comprising A-B, A-B-A or B-A-B block copolymers, wherein
the A block is a biodegradable polyester or poly(ortho ester) and
the B block is polyethylene glycol (PEG), and 2) a polyethylene
glycol (PEG), a PEG derivative, or a mixtures of PEG and a PEG
derivative, wherein at least one of the biodegradable block
copolymers is soluble in an aqueous solution and miscible with the
PEG and/or PEG derivatives. Preferably, the biodegradable block
copolymer drug carriers have a total molecular weight of 2000 to
8000 Daltons, and the weight percentage of the A block is between
50.1% to 83%. The polyethylene glycol (PEG), a PEG derivative, or a
mixtures of PEG and a PEG derivative, preferably have a molecular
weight of 150 to 1100 Daltons. The composition can be administered
as is or after being be dissolved or rapidly reconstituted in an
aqueous vehicle to afford a homogeneous solution or uniform
colloidal system. After the administration, the water soluble
biodegradable block copolymer may or may not form a gel, depending
on molecular weight and hydrophobic block weight percentage of the
block copolymer contained in the composition.
[0017] Another embodiment of the present invention is a liquid
composition comprising 1) one or more biodegradable block copolymer
drug carriers comprising A-B, A-B-A or B-A-B block copolymers,
wherein the A block is a biodegradable polyester or poly(ortho
ester) and the B block is polyethylene glycol (PEG), and 2) a
liquid polyethylene glycol (PEG), a PEG derivative, or a mixtures
of PEG and a PEG derivative; wherein the biodegradable block
copolymer is insoluble in an aqueous solution but soluble in the
PEG and/or PEG derivatives. Preferably, the water insoluble
biodegradable block copolymer drug carriers have a total molecular
weight of 1000 to 10,000 Daltons, and the weight percentage of the
A block is between 20% to 99%. The liquid polyethylene glycol
(PEG), a PEG derivative, or a mixtures of PEG and a PEG derivative,
preferably have a molecular weight of 150 to 1100 Daltons. The
liquid composition is a homogeneous solution or uniform colloidal
system and can be administered directly to a warm blooded animal.
After the administration, the liquid composition forms a drug
containing depot and slowly releases the active substance over a
prolonged period of time and is then decomposed into materials
harmless to the human body and excreted.
[0018] Examples of suitable biodegradable water soluble drug
carriers includes biodegradable ABA- or BAB-type triblock
copolymers, or AB-type diblock copolymers based on biodegradable
polyester or poly(ortho ester) A-blocks and hydrophilic B polymer
block(s) consisting of polyethylene glycol (PEG). The biodegradable
polyester are synthesized from monomers selected from the group
consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid,
D-lactic acid, L-lactic acid, glycolide, glycolic acid,
s-caprolactone, 1,4-dioxan-2-one, s-hydroxy hexanoic acid,
.gamma.-butyrolactone, .gamma.-hydroxy butyric acid,
.delta.-valerolactone, .delta.-hydroxy valeric acid, hydroxybutyric
acids, malic acid, and copolymers thereof.
[0019] Polyethylene glycol (PEG) is also sometimes referred to as
poly(ethylene oxide) (PEO) or poly(oxyethylene) when incorporated
into a block copolymer, and the terms can be used interchangeably
for the purposes of this invention.
[0020] In the case where the A-block(s) are PLA/PLGA polyester, the
lactate content is between about 20 to 100 mole percent, preferably
between about 50 to 100 mole percent. The glycolate content is
between about 0 and 80 mole percent, preferably between about 0 to
50 mole percent. Or, stated differently, when the A-block is PLGA
the glycolate content is between about 1 and 80 mole percent and
preferably between about 1 and 50 mole percent and the lactate
content is between 20 and 99 mole percent and preferably between 50
and 99 mole percent.
[0021] The PEG derivative suitable in the present invention refers
to an ester or ortho ester derivatized PEG having a molecular
weight of 150 to 1100. Preferably, the ester derivatized PEG is a
PEG derivatized from a member selected from the group consisting of
D,L-lactide, D-lactide, L-lactide, D,L-lactic acid, D-lactic acid,
L-lactic acid, glycolide, glycolic acid, .epsilon.-caprolactone,
1,4-dioxan-2-one, .epsilon.-hydroxy hexanoic acid,
.gamma.-butyrolactone, .gamma.-hydroxy butyric acid,
.delta.-valerolactone, 6-hydroxy valeric acid, hydroxybutyric
acids, malic acid, and mixtures thereof. The PEG derivative can
also be a member represented by
R.sup.1--CO--O--(CH.sub.2--CH.sub.2--O).sub.n--CO--R.sup.2 or
R.sup.1--O--(CH.sub.2--CH.sub.2--O).sub.n--R.sup.2 wherein R.sup.1
and R.sup.2 are independently members selected from the group
consisting of H and C.sub.1 to C.sub.10 alkyl and n is an integer
between 3 and 20.
[0022] The biodegradable block copolymer drug carriers suitable for
the present invention can form homogeneous, free-flowing solutions
or uniform colloidal systems in an aqueous vehicle or in the liquid
PEG or PEG derivatives or mixtures thereof. Homogeneous solutions
and uniform colloidal systems of the drug delivery compositions
includes all flowing forms of the compositions of the present
invention, with or without water, drug(s), and any additives or
excipients as necessary to prepare formulations that are
pharmaceutically and therapeutically useful. The drug may be
present as either a true solution or in a colloidal state such as
emulsion or a suspension. All forms can act to facilitate
administration of the drug and enhance the therapeutic effect. Such
therapeutic effects may be optimized by controlling the copolymer
molecular weights, compositions, and the relative ratios of the
hydrophilic and hydrophobic blocks, ratios of drug to copolymer,
ratios of copolymer to PEG and/or PEG derivatives, and both drug
and copolymer concentrations in the final administered dosage form.
Additional advantages of this invention will become apparent from
the following detailed description of the various embodiments.
DETAILED DESCRIPTION OF THE INVENTION
[0023] This invention is not limited to the particular
configurations, process steps, and materials disclosed herein, as
such configurations, process steps, and materials may vary
somewhat. It is also to be understood that the terminology employed
herein is used for the purpose of describing particular embodiments
only, and is not intended to be limiting since the scope of the
present invention will be limited only by the appended claims and
equivalents thereof.
[0024] In this specification and the appended claims, the singular
forms "a," "an," and "the" include plural references unless the
context clearly dictates otherwise. Thus, for example, reference to
a composition for delivering "a drug" includes reference to one,
two, or more drugs. In describing and claiming the present
invention, the following terminology will be used in accordance
with the definitions set out below.
[0025] "Effective amount" means an amount of a drug, biologically
active agent or pharmacologically active agent that provides the
desired local or systemic effect.
[0026] "Copolymer solution", when used in reference to a
biodegradable block copolymer contained in such a solution, shall
mean an aqueous composition having such biodegradable block
copolymer drug carrier either dissolved to form a homogeneous
solution or uniform colloidal system.
[0027] "Drug formulations", "drug delivery compositions", and the
like, shall mean the combination of drug, the block copolymer drug
carrier, and PEG, PEG derivatives, or mixtures of PEG and PEG
derivatives. They shall include all combinations of the drug with
the block copolymer and PEG, PEG derivatives, or mixtures
thereof.
[0028] "Aqueous solution", "aqueous vehicle" and the like, shall
include water without additives or aqueous solutions containing
additives or excipients such as pH buffers, components for tonicity
adjustment, antioxidants, preservatives, drug stabilizers, etc., as
commonly used in the preparation of pharmaceutical
formulations.
[0029] "Drug solution", "solubilized drug", "dissolved drug" and
all other terms that refer to the drug in a solution or dissolved
state includes the drug being present as either a homogeneous
solution, micellar solution, or in a colloidal state such as
emulsion or a suspension. Thus, solubilized drugs and drug
solutions include all flowing forms of the drug delivery
compositions of the present invention. All forms can act to
facilitate administration of the drug and enhance the therapeutic
to effect.
[0030] "Reconstitution" refers to mixing of biodegradable block
copolymer drug carriers and the PEG, PEG derivatives or mixtures
thereof with an aqueous solvent system to create a homogenous
solution or uniform colloidal system. This is in addition to the
more traditional definition of reconstitution where drug and
excipients are mixed with a solvent, usually aqueous, immediately
before administration.
[0031] "Enhanced reconstitution properties" refers to properties
that enable rapid reconstitution of block copolymeric drug carriers
to the final physical state as either a true solution or a uniform
colloidal system. The reconstitution process occurs within a short
period of time, typically between 0.01 minutes to 120 minutes,
preferably within 0.01 minutes to 60 minutes, and most preferably
within 0.01 minutes to 30 minutes.
[0032] "Reverse thermal gelation" is the phenomenon whereby an
aqueous solution of a block copolymer spontaneously increases in
viscosity, and in many instances transforms into a semisolid gel,
as the temperature of the polymer solution is increased above the
gelation temperature of the block copolymer solution. For the
purpose of the invention, the term gel includes both the semisolid
gel state and the high viscosity state that exists above the
gelation temperature. When cooled below the gelation temperature
the gel spontaneously reverses to reform the lower viscosity
polymer solution. This cycling between the solution and the gel may
be repeated indefinitely because the sol/gel transition does not
involve any change in the chemical composition of the polymer
solution. All interactions to create the gel are physical in nature
and do not involve the formation or breaking of covalent bonds.
[0033] "Administration" is the means by which drug formulations are
presented to humans and other warm-blooded animals in effective
amounts, and includes all routes for dosing or administering drugs,
whether self-administered or administered by medical
practitioners.
[0034] "Parenteral" shall mean administration by means other than
through the digestive tract such as by intramuscular,
intraperitoneal, intra-abdominal, subcutaneous, intrathecal,
intrapleural, intravenous and intraarterial means.
[0035] "Depot" means a localized site in the body containing
concentrated active agents or drugs. Examples of formulations that
form depots are gels, implants, microspheres, matrices, particles,
etc.
[0036] "Biodegradable" means that the block copolymer or oligomer
can chemically break down or degrade within the body to form
nontoxic components. The rate of degradation can be the same or
different from the rate of drug release.
[0037] "Drug" shall mean any organic or inorganic compound or
substance having biological or pharmacological activity that can be
adapted or used for a therapeutic purpose.
[0038] "Peptide," "polypeptide," "oligopeptide" and "protein" shall
be used interchangeably when referring to peptide or protein drugs
and shall not be limited as to any particular molecular weight,
peptide sequence or length, field of bioactivity or therapeutic use
unless specifically stated.
[0039] "PLGA" shall mean a copolymer or copolymer radicals derived
from the condensation copolymerization of lactic acid and glycolic
acid, or, by the ring opening copolymerization of lactide and
glycolide. The terms lactic acid and lactate are used
interchangeably; glycolic acid and glycolate are also used
interchangeably.
[0040] "PLA" shall mean a polymer derived from the condensation of
lactic acid or by the ring opening polymerization of lactide.
[0041] "PGA" shall mean a polymer derived from the condensation of
glycolic acid or by the ring opening polymerization of
glycolide.
[0042] "Biodegradable polyester or poly(ortho ester)s" refers to
any biodegradable polyester or poly(ortho ester)s. The polyesters
are preferably synthesized from monomers selected from the group
consisting of D,L-lactide, D-lactide, L-lactide, D,L-lactic acid,
D-lactic acid, L-lactic acid, glycolide, glycolic acid,
.epsilon.-caprolactone, 1,4-dioxan-2-one, .epsilon.-hydroxy
hexanoic acid, .gamma.-butyrolactone, .gamma.-hydroxy butyric acid,
.delta.-valerolactone, .delta.-hydroxy valeric acid, hydroxybutyric
acid, malic acid, and mixtures thereof.
[0043] "Ortho ester" is a carbon which single bonded to three
oxygen atoms covalently.
[0044] The present invention is based on the discovery of PEG, PEG
derivatives or mixtures thereof that can, in minutes, efficiently
accelerate the dissolution of the biodegradable block copolymer
drug carriers into an aqueous medium. The liquid PEG, PEG
derivatives or mixtures thereof of the present invention can also
dissolve the biodegradable block copolymer drug carriers to create
a flowable drug delivery composition. The "PEG, PEG derivatives or
mixtures thereof" of the present invention have a weight averaged
molecular weight of 150 to 1100. The PEG derivative suitable in the
present invention refers to an ester or ortho ester derivatized PEG
having a molecular weight of 150 to 1100. Preferably, the ester
derivatized PEG is a PEG derivatized from a member selected from
the group consisting of D,L-lactide, D-lactide, L-lactide,
D,L-lactic acid, D-lactic acid, L-lactic acid, glycolide, glycolic
acid, .epsilon.-caprolactone, 1,4-dioxan-2-one, .epsilon.-hydroxy
hexanoic acid, .gamma.-butyrolactone, .gamma.-hydroxy butyric acid,
.delta.-valerolactone, .delta.-hydroxy valeric acid, hydroxybutyric
acids, malic acid, and mixtures thereof. The PEG derivative can
also be a member represented by
R.sup.1--CO--O--(CH.sub.2--CH.sub.2--O).sub.n--CO--R.sup.2 or
R.sup.1--O--(CH.sub.2--CH.sub.2--O).sub.n--R.sup.2 wherein R.sup.1
and R.sup.2 are independently members selected from the group
consisting of H and C.sub.1 to C.sub.10 alkyl and n is an integer
between 3 and 20.
[0045] The biodegradable block copolymer drug carriers of the
present invention may be soluble in an aqueous solution, in the
liquid PEG, PEG derivatives or mixtures thereof, or both. Examples
of some of these biodegradable block copolymer drug carriers are
disclosed in U.S. Pat. No. 6,201,072 and pending U.S. patent
application Ser. Nos. 09/559,799; 09/971,074, filed on Oct. 3, 2001
and 09/971,082 filed on Oct. 3, 2001, hereby fully incorporated by
reference. The composition can be administered as is or after being
dissolved or rapidly reconstituted in an aqueous vehicle to afford
a homogeneous solution or uniform colloidal system. After the
administration, the water soluble biodegradable block copolymer may
or may not form a gel, depending on molecular weight and
hydrophobic block weight percentage of the block copolymer
contained in the composition. Water soluble biodegradable block
copolymers are prepared wherein the hydrophilic B-block(s) make up
about 17 to 49.9% by weight of the copolymer and the hydrophobic
A-block or blocks make up about 50.1 to 83% by weight of the
copolymer. The weight ratio of the water soluble biodegradable
block copolymer drug carrier and the PEG, PEG derivatives, or
mixtures of PEG and PEG derivatives, is between 5:1 and 1:99. This
composition can be administered as is or after being quickly
reconstituted in water or an aqueous solution and form a polymer
solution comprising the composition of the present invention in
water or the aqueous solution at a weight ratio between 2:1 and
1:10000. Alternatively, the biodegradable block copolymer may be
insoluble in an aqueous solution but is soluble in the liquid
polyethylene glycol, PEG derivatives or mixtures thereof. In this
case, the liquid composition is a homogeneous solution or uniform
colloidal system and can be administered directly to a warm blooded
animal. After the administration, the liquid composition forms a
drug containing depot and slowly releases the active substance over
a prolonged period of time and is then decomposed into materials
harmless to the human body and excreted. In the liquid composition
of the present invention, the weight ratio of the biodegradable
block copolymer to the PEG, PEG derivatives or mixtures thereof is
preferably within the range of 5:1 to 1:99, and more preferably
within the range of 2:1 to 1:99 and most preferably within the
range of 1:2 to 1:5.
[0046] In one embodiment, the biodegradable drug carrier comprises
ABA-type or BAB-type triblock copolymers, AB-type diblock
copolymers or mixtures thereof, where the A-blocks are relatively
hydrophobic and comprises a biodegradable polyester or poly(ortho
ester), and the B-blocks are relatively hydrophilic and comprises
polyethylene glycol (PEG), said copolymer having a hydrophobic
content of between 50.1 to 83% by weight and hydrophilic content of
between 17 to 49.9% by weight, and an overall block copolymer
molecular weight of between 2000 and 8000. The drug carriers
exhibit water solubility at temperatures below normal mammalian
body temperatures and undergoes reversible thermal gelation to then
exist as a gel at temperatures equal to physiological mammalian
body temperatures.
[0047] In another embodiment, the biodegradable drug carrier is an
ABA-type, BAB-type, or AB-type block copolymer, or mixtures
thereof, where the A-blocks are relatively hydrophobic and
comprises a biodegradable polyester or poly(ortho ester), and the
B-blocks are relatively hydrophilic and comprises polyethylene
glycol (PEG), said block copolymer having a hydrophobic content of
between 50.1 to 65% by weight and a hydrophilic content of between
35 to 49.9% by weight, and an overall block copolymer
weight-averaged molecular weight of between 2400 and 4999. The drug
carriers are water soluble and capable of enhancing the solubility
of drugs, hydrophobic drugs in particular, in water, to form a drug
solution.
[0048] In still another embodiment, the polymeric drug carrier
comprises biodegradable polyester or poly(ortho ester) oligomers,
and particularly PLA/PLGA oligomers having a weight averaged
molecular weight of between 400 and 10,000, mixed with
biodegradable ABA-type or BAB-type triblock copolymers, or AB-type
diblock copolymers having a weight averaged molecular weight of
between 2400 and 4999. The block copolymers have 50.1 to 65% by
weight of the hydrophobic A block(s) comprising biodegradable
polyester or poly(ortho ester)s and 35 to 49.9% by weight of the
hydrophilic B block(s) consisting of polyethylene glycol (PEG).
[0049] The PEG, PEG derivatives or mixtures thereof used in the
present invention dissolves or uniformly mixes with the
biodegradable block copolymer and so reduces the viscosity and
increases the fluidity of the composition. The compositions of the
present invention are flowable liquids or can be easily formulated
with an aqueous vehicle to afford a fluid homogeneous solution or
uniform colloidal system. In the cases that the block copolymeric
drug carrier is insoluble in an aqueous vehicle but soluble in the
liquid PEG and/or PEG derivatives, when in contact with water or
body fluids, the block copolymer forms a drug depot. In cases that
the block copolymeric drug carrier is soluble in an aqueous vehicle
and miscible with the PEG and/or PEG derivatives, the composition
can be easily administered as is or reconstituted with an aqueous
vehicle. After the administration, the block copolymer drug carrier
may or may not form a drug depot. Therefore, the liquid PEG, PEG
derivative or mixtures thereof of the present invention should be a
material that does not cause loss of activity of the
physiologically active substance.
[0050] For purposes of disclosing molecular weight parameters, all
reported molecular weight values are based on measurements by
.sup.1H-NMR or GPC (gel permeation chromatography) analytical
techniques. The reported weight averaged molecular weights and
number averaged molecular weights were determined by GPC and
.sup.1H-NMR, respectively. The reported lactide/glycolide ratios
were calculated from .sup.1H-NMR data. GPC analysis was performed
on a Styragel HR-3 column, or equivalent, calibrated with PEG
standards using RI detection and chloroform as the eluent, or on a
combination of Phenogel, mixed bed, and 500 .ANG. columns
calibrated with PEG standards using RI detection and
tetrahydrofuran as the eluent for the ABA and BAB triblock
copolymers.
[0051] ABA-type and BAB-type triblock copolymers, and AB-type
diblock copolymers may be synthesized by ring opening
polymerization, or condensation polymerization. Additionally, the
B-blocks may, in certain instances, be coupled to the A-blocks by
ester or urethane links and the like. Condensation polymerization
and ring opening polymerization procedures may be utilized as may
the coupling of a monofunctional hydrophilic B block to either end
of a difunctional hydrophobic A block in the presence of coupling
agents such as isocyanates. Furthermore, coupling reactions may
follow activation of functional groups with activating agents, such
as carbonyl diimidazole, succinic anhydride, N-hydroxy succinimide,
p-nitrophenyl chloroformate and the like.
[0052] The hydrophilic B-block is formed from PEG of an appropriate
molecular weight. PEG was chosen as the hydrophilic B-block because
of its unique biocompatibility, nontoxic properties,
hydrophilicity, solubilization properties, and rapid clearance from
a patient's body. The hydrophobic A-blocks are utilized because of
their biodegradable, biocompatible, and solubilization properties.
The in vitro and in vivo degradation of hydrophobic, biodegradable
polyester or poly(ortho ester) A-blocks are well understood and the
degradation products are readily metabolized and/or eliminated from
the patient's body.
[0053] Drugs that may be incorporated with the drug delivery
compositions of the present invention can be any bioactive agent,
but particular advantage is achieved with bioactive agents having
limited solubility or dispersibility in an aqueous or hydrophilic
environment, or any bioactive agent that requires enhanced
solubility or dispersibility. Without limiting the scope of the
present invention, suitable drugs include those drugs presented in
current edition of Goodman and Gilman's "The Pharmacological Basis
of Therapeutics" or the current edition of The Merck Index. Both
volumes list drugs suitable for numerous types of therapeutic
applications, including drugs in the following categories:drugs
acting at synaptic and neuroeffector junctional sites, drugs acting
on the central nervous system, drugs that influence inflammatory
responses, drugs that affect the composition of body fluids, drugs
affecting renal function and electrolyte metabolism, cardiovascular
drugs, drugs affecting gastrointestinal function, drugs affecting
uterine motility, chemotherapeutic agents for parasitic infections,
chemotherapeutic agents for microbial diseases, antineoplastic
agents, immunosuppressive agents, drugs affecting the blood and
blood-forming organs, hormones and hormone antagonists,
dermatological agents, heavy metal antagonists, vitamins and
nutrients, vaccines, oligonucleotides and gene therapies.
[0054] Incorporating one or more drugs mentioned in the above
categories with the compositions of the present invention to form
drug delivery compositions which can be dissolved or easily
reconstituted to form an aqueous solution or uniform colloidal
system can be achieved by simply adding the drug to the liquid
composition or an aqueous solutions of the compositions of the
present invention, or by mixing the drug with the compositions of
the present invention and thereafter adding water or an aqueous
solution to form a solution or uniform colloidal system.
[0055] Mixtures of the compositions of the present invention with
peptide/protein drugs, and/or other types of drugs, may be prepared
as flowable drug delivery formulations or formulations that may be
easily reconstituted in the form of a solution or dispersion. The
flowable formulation is then administered parenterally, topically,
transdermally, transmucosally, inhaled, or inserted into a cavity
such as by ocular, vaginal, transurethral, rectal, nasal, oral,
peroral, buccal, pulmonary or aural administration to a patient.
Many of the solubilized drug formulations prepared by implementing
the present invention may be diluted in an i.v. bag or by other
means, and administered to a patient for an extended period,
without precipitation of the drug. Due to the biocompatibility of
the materials and the free flowing nature of the system at
physiological temperatures, this system will cause minimal toxicity
and minimal mechanical irritation to the surrounding tissue.
[0056] A distinct advantage to the compositions of this invention
lies in the ability of PEG, PEG derivatives or mixtures thereof to
reduce the viscosity of the biodegradable block copolymer drug
carriers into a form that is flowable liquid or can be quickly
reconstitutable in water or an aqueous solution to form a solution
or uniform colloidal system for drug delivery. In one possible
configuration, a dosage form comprised of a solution of the block
copolymer drug carrier and a PEG, PEG derivatives or mixtures
thereof that contains drug is administered to the body. In another
possible configuration, the drug delivery composition of the
present invention may be quickly dissolved or reconstituted by
using water or other aqueous solutions.
[0057] The only limitation as to how much drug can be dissolved or
dispersed in the drug delivery composition of the present invention
is one of functionality, namely, the drug:copolymer ratio may be
increased until the properties of the mixture are adversely
affected to an unacceptable degree, or until to the properties of
the system are adversely affected to such a degree as to make
administration of the system unacceptably difficult. Generally
speaking, it is anticipated that in most instances where
dissolution is desired, the drug will be present at between about
10.sup.-6 to about 100 percent by weight of the combined weight the
block copolymer drug carrier and the PEG, PEG derivatives or
mixtures thereof, with ranges of between about 0.001% to 25% by
weight being the most common. For example, having the drug present
at 100% by weight of the combined weight of the block copolymer
drug carrier and the PEG, PEG derivatives or mixtures thereof means
that the drug and combined weight the block copolymer drug carrier
and the PEG, PEG derivatives or mixtures thereof are present in
equal amounts (i.e., equal weights). Generally speaking, it is
anticipated that in most instances where dispersion is desired, the
upper drug:copolymer ratio could substantially exceed the range
noted above for dissolution. These ranges of drug loading are
illustrative and will include most drugs that may be utilized in
the present invention. However, such ranges are not limiting to the
invention should drug loadings outside this range be functional and
effective.
[0058] The present invention thus provides compositions comprising
biodegradable block copolymer drug carriers and PEG, PEG
derivatives or mixtures thereof that are flowable liquids or can be
rapidly reconstituted in an aqueous vehicle to afford useful forms
that may be either homogeneous true solutions or uniform colloidal
systems. The drug solution formed with the drug delivery
compositions of the present invention has desirable physical
stability, therapeutic efficacy, and toxicology. The PEG, PEG
derivatives or mixtures thereof of the present invention can be
used for water soluble or water insoluble block copolymeric drug
carriers, particularly for biodegradable di- or triblock copolymers
that have reverse gelation properties and/or polymers that can
enhance the solubility of drugs, especially hydrophobic drugs.
[0059] The following are examples that illustrate preferred
embodiments of the invention but are intended as being
representative only.
Example 1
[0060] PEG-300 (107.6 g) was placed in a 250-mL round bottom flask
and dried under vacuum (0.2 torn, 90.degree. C.) for 3 hours.
D,L-Lactide (33.4 g) and glycolide (9.0 g) was added and the
head-space was replaced by dried nitrogen. The mixture was brought
to 135.degree. C. and the reaction was initiated by adding stannous
octoate (20 mg) via a dry syringe. The reaction mixture was allowed
to stir under dry nitrogen at 155.degree. C. for four additional
hours. Residual monomers were removed under vacuum (0.2 torr,
90.degree. C., 2 hr). The resulting PEG derivative (D1) was a clear
free-flowing liquid.
Example 2
[0061] Following the procedure described in Example 1, the
following PEG derivatives were prepared.
TABLE-US-00001 TABLE 1 PEG derivatives synthesized by the method
described in Example 1 PEG weight Glycolide D,L-Lactide ID PEG
(gram) (gram) (gram) D2 PEG200NF 30.0 7.62 28.38 D3 PEG200NF 33.33
5.64 21.02 D4 PEG300NF 57.14 4.84 18.02 D5 PEG600NF 50.0 4.23 15.75
D6 Triethylene 50.0 4.23 15.77 glycol D7 PEG300NF 50.25 19.75 -- D8
PEG300NF 86.15 24.67 9.19 D9 PEG300NF 100.5 -- 39.5
Example 3
[0062] PEG-300 (40 g) was placed in a 250-mL round bottom flask.
Moisture was removed by drying under vacuum (0.2 torr) at
90.degree. C. for 3 hours. Acetic anhydride (30 g) was added and
the reaction mixture was brought to reflux under nitrogen over 48
hours. Excess acetic anhydride was removed by vacuum distillation
at 100.degree. C. for 24 hours. The resulting PEG derivative (D10)
was a clear, free-flowing liquid.
Example 4
[0063] This example illustrates the synthesis of the ABA-type
triblock copolymer PLGA-PEG-PLGA by ring opening
copolymerization.
[0064] PEG 1000 NF (65.3 g) and PEG 1450 NF (261 g) was dried under
vacuum (1 mmHg) at 130.degree. C. for 5 hours. D, L-Lactide (531.12
g) and glycolide (142.6 g) were added to the flask and heated to
155.degree. C. to afford a homogenous solution. Polymerization was
initiated by the addition of 250 mg stannous octoate to the
reaction mixture. After maintaining the reaction for five hours at
145.degree. C., the reaction was stopped and the flask was cooled
to room temperature. Unreacted lactide and glycolide were removed
by vacuum distillation. The resulting PLGA-PEG-PLGA copolymer
mixture (ABA 1) had a weight averaged molecular weight (Mw) of 4255
as measured by GPC. This triblock copolymer mixture is water
soluble at room temperature. A 23% by weight aqueous solution of
this triblock copolymer mixture had a gel temperature between
30.degree. C. and 37.degree. C.
Example 5
[0065] Using the procedure described in Example 4, the following
copolymers or copolymer mixtures were synthesized:
TABLE-US-00002 TABLE 2 Copolymers synthesized using the procedure
described in Example 3 LA/GA PEG1/ Block Molar PEG1 PEG2 PEG2 MW
Copolymer Ratio MW MW wt Ratio (Dalton) Remarks PLG-PEG-PLG 75/25
1000 -- 100/0 4250 Water (ABA 2) soluble PLG-PEG-PLG 75/25 1450 --
100/0 3950 Water (ABA 3) soluble PLA-PEG-PLA 100/0 1000 1450 10/90
3980 Water (ABA 4) soluble PLG-PEG-PLG 75/25 1450 -- 100/0 7540
Water (ABA 5) insoluble PLA-PE-PLA 100/0 1000 600 80/20 6500 Water
(ABA 6) insoluble
Example 6
[0066] AB diblock copolymer was synthesized by placing 25.7 g of
PEG-Me (Mw: 2000) in a 250 mL 3-neck round bottom reaction flask.
Water was removed by heating in an oil bath (155.degree. C.) under
vacuum (0.5 torr) for 3 hours. The reaction flask was then raised
out of the oil bath and the vacuum was released.
[0067] D,L-Lactide (32.0 g) was weighed and added to the reaction
flask. The headspace was replaced with dry nitrogen by repeated
evacuation and flushing with dry nitrogen 5 times.
[0068] The flask was then lowered and immersed in a 155.degree. C.
oil bath. Once the content was melted and the internal temperature
reached 150.degree. C., 2 drops (200 ppm) of stannous
2-ethylhexanoate was added to initiate the polymerization. The
reaction mixture was stirred using an overhead stirrer for 8 hours
at a rate of 100-200 rpm. The temperature was then reduced to
140.degree. C., and the residual monomer was removed under reduced
pressure (<1 torr) over 1 hour. The residue is a translucent,
off-white solid having a molecular weight of 5450.
[0069] One gram of the diblock copolymer was added to 4 grams of
PEG derivative (D10) to afford a clear and free flowing liquid.
Upon addition of the mixture to 37.degree. C. water, the mixture
turned cloudy due to apparent precipitation of the water insoluble
diblock copolymeric component.
Example 7
[0070] Me-PEG (MW 550; 48.6 g) was transferred into a 250 mL 3-neck
round bottom reaction flask. The oil bath was heated to 100.degree.
C. The molten PEG-Me was stirred under vacuum for 5 hours to remove
water. The reaction flask was then raised outside of the oil bath
and the vacuum was released. D,L-Lactide (97.68 g) and glycolide
(26.47 g) were weighed and added the reaction flask. The headspace
was replaced with dry nitrogen. The flask was then immersed into a
155.degree. C. oil bath. Once the D,L-lactide was melted and the
temperature inside the reaction flask reached 150.degree. C., 2
drops (200 ppm) of stannous 2-ethylhexanoate was added to the
reaction flask. The reaction was stirred continuously for 8 hours
at a rate of 100-150 rpm.
[0071] The oil bath temperature was reduced to 140.degree. C. and
the reaction flask was attached to vacuum (<1 torr) for an hour
to remove residual monomer. The diblock copolymer had honey-like
consistency with molecular weight of 2010. The residue (145 g) was
added to 1,6-diisocynatohexane (6.06 g) via an oven dried syringe
and the reaction mixture was allowed to stir at 140.degree. C. for
2 additional hours. The residue was purified by dissolving the
polymer in water and precipitation at 70.degree. C. Water was
removed by lyophilization and the residual BAB triblock copolymer
had a molecular weight of 4250.
[0072] One gram of the polymer was dissolved in 4 gram of PEG
derivative (D 4) and the mixture was added to 25 mL of warm water
(37.degree. C.) via a 24-G needle. Upon addition of the mixture to
37.degree. C. water, the mixture turned cloudy due to apparent
precipitation of the water insoluble diblock copolymeric
component.
Example 8
[0073] The use PEG derivatives for reconstitution are illustrated
in this example.
[0074] The PEG derivative (1.5 g) prepared from Example 1 were
added to 1 gram of PLGA-PEG-PLGA triblock copolymer prepared from
Example 4. The two components were intimately mixed into a
homogeneous mixture. To the mixture, water for injection (5 g) was
added shaken. The mixture took 1 minute to reconstitute. The
resulting aqueous solution had a gelation temperature at 30.degree.
C. and 37.degree. C.
[0075] Zinc insulin (5 mg) was reconstituted with 5 mL of the
aqueous solution and the solution was injected into 37.degree. C.
water. The solution rapidly gelled.
Example 9
[0076] Zn-insulin (5 mg) is suspended a mixture composed of a
triblock copolymer (ABA 6; 1 g) dissolved in 6 g of PEG derivative
(D 2). The mixture is a free-flowing liquid. One mL of the
suspension is injected into warm water (25 mL; 37.degree. C.). Upon
addition of the mixture to 37.degree. C. water, the mixture turned
cloudy due to apparent precipitation of the water insoluble
triblock copolymeric component.
Example 10
[0077] The PEG derivatives (D6; 4 g) were added to 1 gram of
PLGA-PEG-PLGA triblock copolymer (ABA3). Also added to the mixture
was 50 mg of paclitaxel. The mixture was intimately mixed into a
homogeneous mixture at ca. 40.degree. C. for ca. 20 minutes. The
mixture was a clear free flowing liquid. One gram of the mixture
was added to a beaker containing 25 mL of warm water (37.degree.
C.). The mixture apparently dissolved rapidly to afford a clear
solution or uniform colloid.
Example 11
[0078] The PEG derivative (3 g) from Example 1 were intimately
mixed with 1 gram of PLGA-PEG-PLGA triblock copolymer (ABA3) and
0.08 g of poly(D,L-lactate-co-glycolate) (MW 1200) into a
homogeneous mixture. Paclitaxel (75 mg) was dissolved into the
mixture with gentle stirring at ca. 45.degree. C. After
equilibrated to ambient temperature, water for injection (5 g) was
added and the mixture was shaken. The mixture apparently dissolved
rapidly to afford a clear solution or uniform colloid.
Example 12
[0079] This example illustrate the synthesis of poly(ortho ester)
AB diblock copolymer.
[0080] Dried 1,4-cyclohexanedimethanol (2.6 g), PEG 2000 methyl
ether (4 g) is heated at 70.degree. C. with DETOSU
(3,9-bis(ethylidene)-2,4,8,10-tetraoxaspiro[5,5]undecane; 4.35 g)
in dried 1,4-dioxane (100 mL) over 8 hour. The solvent is removed
under vacuum (0.5 torr; 70.degree. C.) over 40 hours. The resulting
poly(ortho ester) AB diblock copolymer is a transparent
copolymer.
Example 13
[0081] This example illustrates the synthesis of PEG ortho ester
derivative. PEG 300 (25.0 g) is heated in a round bottomed flask
under vacuum at 90.degree. C. for 3 hours to remove residual water.
Molten DETOSU
(3,9-bis(ethylidine)-2,4,8,10-tetraoxaspiro[5,5]undecane) (4.0
grams) is added to the flask through an oven dried syringe. The
mixture is allowed to heat at 90.degree. C. over 5 hours. The
resulting PEG ortho ester derivative is a clear liquid.
Example 14
[0082] This example illustrates the use of PEG ortho ester
derivative. Paclitaxel (50 mg) is dissolved with mild heating into
a mixture of PEG derivative (15 g) synthesized in Example 13 and an
AB diblock poly(ortho ester) copolymer (3 g) prepared in Example
12. The resulting mixture is a clear liquid. Upon addition of the
mixture to 37.degree. C. water, the mixture turned cloudy due to
apparent precipitation of the water insoluble diblock copolymeric
component.
[0083] The above description will enable one skilled in the art to
make a composition comprising biodegradable block copolymer drug
carriers and PEG, PEG derivatives, or a mixtures thereof, said
composition is a flowable liquid or can be rapidly reconstituted in
an aqueous vehicle to homogeneous solutions or uniform colloidal
systems. Although the drug delivery compositions are described to
show the functionality of the compositions of the present
invention, these descriptions are not intended to be an exhaustive
statement of all drug carriers that can be rendered soluble and/or
constitutable by the compositions of the present invention.
Certainly, numerous other drug carriers or drugs from various
categories of therapeutic agents are well suited for the drug
delivery compositions described in this invention. It will be
immediately apparent to one skilled in the art which various
modifications may be made without departing from the scope of the
invention that is limited only by the following claims and their
functional equivalents.
* * * * *